But in a perplexing twist, the drug did show a significant benefit in about 15 percent of patients in the trial who were not taking other standard Alzheimer's drugs, according to the findings released on Wednesday at the Alzheimer's Association International Conference in Toronto.

LMTX was ineffective in a clinical trial of 891 patients with Alzheimer's disease (AD), although a post hoc analysis in a small subgroup of patients showed a benefit for those taking no other medications for AD (when compared to an inappropriate control group).

As the name implies, TauRx is developing Alzheimer's treatments based on disrupting tau protein, which accumulates in pathological tangles in the brain. Tau aggregation inhibitors are presumed to disrupt these tangles, thereby slowing neurodegeneration and memory loss. The degradation of tau aggregates in vitro was first demonstrated 20 years ago (Wischik et al., 1996), using the stain methylene blue. LMTX is a variant of methylene blue, which turns urine blue. For that reason, the placebo group in the TauRx trial received a tiny amount of the drug for blinding purposes.

TauRx Therapeutics Ltd today announced Phase 3 clinical trial results that show treatment with LMTX®, the company's novel tau aggregation inhibitor, had a marked beneficial effect on key measures of Alzheimer's disease in patients with mild or moderate forms of the disease.

While the TRx-237-015 study in 891 subjects failed to meet its co-primary endpoints, clinically meaningful and statistically significant reductions in the rate of disease progression were observed across three key measures in patients who were treated with LMTX® as their only Alzheimer's disease medication. These three key measures comprised a cognitive assessment (ADAS-Cog), a functional assessment (ADCS-ADL) and an assessment of the level of brain atrophy (lateral ventricular volume, LVV, as measured by MRI). An abstract of the results will be presented during an open session at the 2016 Alzheimer's Association International Conference (AAIC) in Toronto, Canada this afternoon by Dr. Serge Gauthier, CM, MD.

The ADCS-ADL was originally a secondary outcome measure, and hippocampal volume (not reported) was included as an “Other” outcome measure along with the lateral ventricle volume measurements. Keep in mind these results are preliminary (not peer-reviewed). However, given the possibility of a true positive treatment effect, I can understand why publication would be of secondary importance. There should be no delay in starting AD patients on an effective new and proven treatment (which this is not).

It took a while to find the conference abstract by Gaultier et al. (2016), but an excerpt is below. The actual results were not included — the abstract aimed to “highlight the potential therapeutic value” of LMTX (also called LMTM and TRx-0237) — but the text did mention the “85% were taking approved AD treatments” aspect of the study.

LMTM (TRx-0237) is a novel stabilized reduced form of the methylthioninium moiety with potential for efficacy in treatment of Alzheimer's disease. ... It acts as a selective tau aggregation inhibitor in vitro and in transgenic mouse models The present 15-month double-blind, placebo-controlled trial (NCT01689246) was performed in patients with probable AD, MMSE score in the range 14-26, Clinical Dementia Rating 1-2 and age < 90 years. Patients were randomized 3:3:4 to receive oral LMTM at doses of 150 or 250 mg/day or placebo (containing 8 mg/day, to maintain blinding) respectively. Primary efficacy outcomes were change from baseline on cognitive (ADAS-Cog) and functional (ADCS-ADL) scores. Three-monthly assessment included magnetic resonance imaging (MRI) as a disease modifying outcome. Other secondary outcomes included ADCS-CGIC and MMSE. Results: A total of 891 patients were randomized, of whom 62% were female. Approved AD treatments were being taken in 85%. The mean age was 70.6 (SD 9.0) years and baseline MMSE score was 18.7 (SD 3.4). ... The study efficacy and safety outcomes will be reported. The outcomes of this phase 3 trial will highlight the potential therapeutic value of tau aggregation inhibitor therapy in AD. A second phase 3 trial of LMTM for AD will be completed and reported later in 2016.

[The entire abstract with authors and affiliations is at the end of this post.]

The 15% who benefited from LMTX® were the patients who were not taking any other medications for dementia (e.g., acetylcholinesterase inhibitors). This monotherapy subgroup was compared to the entire placebo group, not to the subgroup of placebo patients not on any other dementia meds (as pointed out by @bengoldacre). It was nice to read critical coverage of the TauRx spin (and media reporting) at Forbes, BuzzFeed, and Quartz.

Meanwhile, New Scientist updated their headline (and url) to more accurately reflect reality.

Is it worthwhile for TauRx to pursue a proper clinical trial of LMTX as a monotherapy? Maybe. The big mystery is why LMTX didn't work in patients taking the usual medications for dementia. There's no convincing mechanism to explain that odd result (Wischik: “other Alzheimer’s treatments help to clear toxic material out of the brain, and may also clear away LMTX too”). Or it could be a p-hacked false positive, or a function of milder severity or diagnostic issues or study site in the 15%. If TauRx is truly confident that LMTX taken alone can slow the progression of AD by 80%, then run another randomized controlled study where LMTX + no AD meds is compared to placebo + no AD meds.

On the main primary results slide, disease progression curves for both doses of drug and the placebo were practically identical. Scientists’ disappointment at this finding soon turned into disbelief when Gauthier went on to present a subgroup analysis that held no statistical credence yet purported to show a strong benefit on cognition and brain atrophy.

Friday, July 22, 2016

Brain is the most complex organ in the human body & serves as the center of the nervous system. Brain is the amazing organ as we go deeper we realize the miracles of the GOD. If all information of all books in the world is loaded into the brain, human brain will never be full. Do you know, we are using at the most 4% to 5% of potential of our brain?. Potential of human brain is beyond our imagination. Full potential is a result of proper education (mental development). Think what will happen if we use whole brain?

Mid-brain activation is a method to stimulate and balance the left and right brains. Mid brain Activation allows the middle brain act as a control panel for left and right hemispheres. This activates both parts of the brain and enhances the capacity and ability to learn.

What is the middle brain?

Mid brain manages functions of left and right brain. Mid brain is the ‘bridge’ between left and right hemispheres. [No, that would be the corpus callosum.] Once the mid brain gets activated, information will exchange more efficiently in between both hemispheres which leads to more efficient in learning and absorbing information.Mid brain activation allows the brain to function as a whole, rather than only utilizing one part of the brain.

3. Left Brain is Beta, Right Brain is Alpha.

Did you know that each hemisphere has a unique pattern of oscillatory brain activity, operating at separate frequency bands?

One type of brain function belongs to left brain which operates at Beta wave frequency (14Hz to 30Hz cycles/sec). This is the brain we are most familiar with, having developed this brain in traditional academy settings. ... The right brain works at Alpha wave frequency (8 to 13 hertz cycles per second). This is the frequency of the brain associated with a relaxed alert state of mind such as in meditation, just before getting out of bed or while listening to music. It is not the type of brain activity which determines whether something is right or left brain oriented, but rather the brain wave that is operating at the time (Alpha or Beta).

In order to awaken this part of the brain, it is necessary to stimulate a hormonal discharge by sending a special vibration. For this scientific alpha-theta level music are played where apparently only children can receive these waves effectively. In general, theta and alpha waves belong to babies and children. Since these waves belong to the subconscious mind babies and children feel easier to learn something or receive and follow somebody else’s words.

During the mid-brain activation, a child learns how to enter the condition of meditative trans in order to be able to ”see” with eyes closed (Blind-folded).
. . .

Blindfold activation ... is a form of extra sensory perception.Our activated mid-brain’s brain-wave may detect objects nearby & appears in our mind as a form of visualization.Science have proven that even animals are able to perform such ability when moving around or looking for food.e.g.Bats.In human beings , in Blind-fold activation intuition play an important role.

Children will be given an opportunity to do activities of ALPHA & THEATA level vigorously throughout the workshop.Conventional school emphasize predominantly on BETA waves & neglect the importance of ALPHA & THEATA wave learning environment which are for more conducive.

The benefits of their Brain Stimulation program also include improvements in attention, mood, motivation, energy, pain, sleep, performance enhancement, and stress reduction.

Saturday, July 16, 2016

I retired aged 65 – I am known for being very pro-retirement. Older scientists should advise, if asked, by the next generation, which they trained. They should refrain from occupying leadership positions or directing implementation – the time for that is past.

This is an important public stance to take in a time of dwindling resources and opportunities for junior scientists. On the one hand, with the steady increase in life expectancy since 1935, many aging Boomers plan to work well into their 70s. But on the other hand, this glut of working elders deprives many talented young researchers entrée into tenure track positions. The fact that a senior scientist wants to move aside to allow the next generation to occupy leadership positions is notable, in my view.

“I hope that you are at least partly convinced that it is not impossible to build a brain. We can do it within 10 years, and if we do succeed, we will send to TED, in 10 years, a hologram to talk to you”.

Frackowiak found the post “scurrilous” and specifically objected to Schneider's mischaracterization of his own retirement as “resigning” from the HBP:

I note one mistake that could easily have been checked. Makes me wonder about the accuracy of this scurrilous blog. I did not resign from the HBP. I remain a task leader in the Medical Informatics Platform.

With this notice, Frontiers states its awareness of several complaints and serious allegations surrounding the article “Human and Environmental Dangers Posed by Ongoing Global Tropospheric Aerosolized Particulates for Weather Modification” published on 30 June 2016. Our Chief Editors, Joav Merrick and Anwar Huq, will direct an investigation in full accordance with our complaints procedures. The situation will be updated as soon as the investigation is complete.

Based on information discovered after publication and reported to
Frontiers in July 2016, the article was examined, revealing that the
complaints were valid and that the article does not meet the standards
of editorial and scientific soundness for Frontiers in Public Health.
The retraction of the article was approved by the Field Chief Editor of
Frontiers in Public Health and the Specialty Chief Editor of
Environmental Health. The author considers the retraction to be
unwarranted and therefore does not agree to the statement.

What does this have to do with the HBP?? Nothing. It came along as part of the larger anti-Markram package.

Friday, July 01, 2016

Contemporary consumers of science infotainment “need” to understand that the brain responds to modern technology in an unprecedented and potentially sinister way. Or at least, that's what you'd think, based on the number of books and essays on how The Internet and Digital Technologies are destroying our brains. The latest entrée into this lucrative genre of mild techno-paranoid is from Elsevier, with their press release about a poorly controlled observational study in a relatively obscure journal:

Sending text messages on a smartphone can change the rhythm of brain waves, according to a new study published in Epilepsy & Behavior.
. . .

Dr. Tatum, professor of neurology and director of the epilepsy monitoring unit and epilepsy center at Mayo Clinic in Jacksonville, Florida found a unique 'texting rhythm' in approximately 1 in 5 patients who were using their smartphone to text message while having their brain waves monitored.

But here's what we don't know about the 'texting rhythm'. We don't know:

That the signal represents brain activity, rather than a biological artifact (e.g., eye movements) or an electromagnetically-induced artifact produced by the smartphone

That the 'texting rhythm' has never been seen before, given the lack of systematic studies

That it occurs in people without epilepsy

That it has any direct relation to how we think

In a series of two [largely overlapping]studies, Tatum and colleagues (2016a, 2016b) recorded noninvasive EEG (brainwave) activity from inpatients undergoing continuous video monitoring for potential seizure activity. In the more recent paper (2016b), records from 129 texting patients were reviewed for the presence of a reproducible texting rhythm (TR), defined as “a distinct, paroxysmal, time-synched, rhythmic, generalized, frontocentral, 5–6 Hz, monomorphic, theta rhythm repeatedly induced by text messaging” (based on their 2016a study with 100 patients).

Fig. 1 (adapted from Tatum et al., 2016b). (B) unilateral texting with the right hand (picture insert) during video-EEG monitoring. Note the presence of the TR as a 5–6-Hz frontocentral monomorphic rhythm (blue boxes) at the start and termination of texting (solid blue arrows).

It's hard to see what's going on here, so I've zoomed in on the lower box, which shows activity from two bipolar derivations. The Fp1-F3 trace shows eye movements and the F3-C3 trace shows the TR. It appears to be more rhythmic in these left hemisphere electrodes contralateral to the texting hand, but the TR can also be seen in the F4-C4 derivation in Fig 1B.

Although I'm just making qualitative guesses here, I don't think the EEG was quantified with spectral power or time-frequency analyses. In other words, epochs of EEG during texting vs. other activities (audio telephone use, thumb/ﬁnger movements, cognitive testing/calculation, scanning eye movements, and speech/language tasks) were eyeballed for the presence or absence of TR. We learn that the TR lasted from 2 sec to continuous runs of >10 sec. We don't know the number or duration of epochs during the various control activities, but the authors declared a startling significance level:

The TR was highly speciﬁc to this text messaging (p < 0.0001). A similar waveform during baseline activation with motor, speech/language, and cognitive tasks performed independently was absent in all patients and was not observed during auditory–verbal smartphone communication (p < 0.0001).

The TR didn't habituate with repeated texting, wasn't specific to iPhone vs. Android, and “was observed in a patient using an iPad, though we did not observe it during the use of a laptop.”

But most texting patients undergoing video EEG monitoring did not show a TR. The percentage of patients with a TR was 24.5% (24 out of 98) and 22.6% (7 out of 31) in a separate Chicago cohort (Tatum et al, 2016a), and only 20.9% (27 of 129) in the 2016b paper. Having a TR wasn't related to age, sex, type of seizure (focal, generalized, epileptic, non-epileptic), or presence/absence of brain lesion on MRI. And we have absolutely no explanation for why that might be, which inspired this hilarious, overly honest headline:

Does using a smartphone fundamentally alter the way that your brain works? ...a group of researchers at the Mayo Clinic recently discovered that text messaging elicits a change in the regular rhythm of brain waves, completely different than the waveforms created by any other activity.

“The big deal with discovering this ‘texting rhythm’ is that the number of new brain waves that are identified on EEG are extremely rare at this point in time,” Dr. William Tatum, the lead author of the study, tells Digital Trends.

Dr. Tatum says that the new brain waves were discovered by accident when analyzing the day-to-day cortical rhythms of people suffering from epilepsy. This discovery triggered an investigation into the neurological effects of smartphone use, which ultimately grew to include nearly 130 participants over a period of 16 months. Only around one in five participants demonstrated the “texting rhythm,” although it didn’t appear to conform to any single gender, ethnicity or age group. Nor is it known exactly what aspect of texting prompts the effect: since text messaging includes a variety of different skills, such as finger dexterity, formulating succinct communications and more.

So does that mean I believe the TR is real? I'll withhold judgment until the results from carefully controlled, quantitatively analyzed, statistically rigorous experiments in participants with and without epilepsy are in. Meanwhile, speculating on the origin, meaning, or relevance of the 'texting rhythm' is premature...

“The question we’re trying to answer right now is whether this is a destructive process or an active process,” Dr. Tatum says. “We think it’s probably an active process through an entrainment of normal cortical rhythms. What’s strange is that it appears to be a destructive frequency that’s more typically identified in people that have a slowing of their brain waves.”

About Me

Born in West Virginia in 1980, The Neurocritic embarked upon a roadtrip across America at the age of thirteen with his mother. She abandoned him when they reached San Francisco and The Neurocritic descended into a spiral of drug abuse and prostitution. At fifteen, The Neurocritic's psychiatrist encouraged him to start writing as a form of therapy.